Project Summary: In normal pregnancy resetting of volume control systems maintains elevated blood volume, and arterial baroreflex control of sympathetic outflow is adapted to protect against hypertension, at the expense of compensatory responses to hypotensive stimuli (although baseline sympathetic tone to the heart and vasculature is mildly elevated). A hallmark of serious hypertensive disorders in pregnancy is the lack of these adaptations and exaggerated sympathoexcitation. The long term goal of research in the P.I.'s laboratory is to understand mechanisms for effects of ovarian hormones on central nervous system control of sympathetic nerve activity. Aims of the current project are to determine: 1.) If pregnancy is associated with differential changes in inhibitory inputs to regions of the brain containing sympathetic projection neurons; 2.) if nitric oxide (NO) modulation of the inhibitory neurotransmitter GABA on sympathetic projection neurons differs between pregnant and nonpregnant rats; and 3.) if the neuroactive steroid metabolite of progesterone, 3-OH, DHP, contributes to apparent differences in GABAergic inhibition in different brain regions containing presympathetic neurons. A strength of the proposed experiments is the varied expertise of participating investigators which allows for a multilevel approach at the whole animal, cell population, single cell, and molecular level. Hemorrhage and hypertensive disorders during pregnancy and delivery contribute significantly to maternal mortality (~30% of deaths) and morbidity. Thus, results from these experiments have important national health implications.